The present invention relates to a process for the preparation of (pyridinylidene)-phthalides and, more particularly, relates to a process for preparing (pyridinylidene)-phthalides starting from 3-oxo-1,3-dihydro-isobenzofuran-1-carboxylic acids and pyridinecarbaldehydes. The (pyridinylidene)-phthalides are known compounds, described in the literature.
In the International patent applications WO 98/35958 in the name of Novartis and WO 00/05218 in the name of the same applicant various (pyridinylidene)-phthalides are used as useful intermediates for preparing phthalazines endowed with inhibitory activity of angiogenesis and PDE4 enzyme respectively.
Several methods for synthesizing arylidenephthalides are known and some of them, particularly, have been employed for preparing (pyridinylidene)-phthalides.
For instance J. Ploquin et al. In J. Het. Chem. (1980), 17, 961 report the preparation of (pyridinylidene)-phthalides by hot condensation between phthalic anhydride and methyl-pyridines. This reaction, however, has a poor applicative interest because, besides presenting poor yields, it is limited to obtain unsubstituted or symmetrically substituted on the phthalic ring derivatives. In fact an asymmetrical substitution would inevitably lead to the formation of regioisomers difficult to separate.
A different process for preparing, inter alia, (pyridinylidene)-phthalides also asymmetrically substituted, reported in the already cited patent application WO 00/05218, is based on the Wittig condensation between a phosphonium salt XI and an aldehyde XII as here depicted: 
wherein A also represents pyridine and Zxe2x80x2 can be absent.
Nevertheless this process, although it has a pratically quantitative yield, presents a series of disadvantages that make it of poor industrial interest.
In fact the preparation of the phosphonium salt XI, that occurs according to the following schema: 
shows some critical points. Particularly the radicalic bromuration reaction of XI is strongly esothermic, the resultant bromurated product X is unstable and therefore it must be quickly used in the reaction with triphenylphosphine to give the phosphonium salt XI.
Lastly during this last step the molecular weight of the substrate increases considerably involving an undesired increase of the reaction mass. Besides, in the subsequent Wittig reaction the formation of equimolar quantities of phosphineoxide occurs that ulteriorly complicates the synthetic feasibility.
All these problems make the above mentioned process hardly practicable at industrial level. Among the known alternative methods for preparing arylidenephthalides it is of particular interest the one described by R. H. Pager et al. in Tetrahedron, (1984), 40, 1517 that uses differently substituted benzaldehydes (4) and 3-oxo-1,3-dihydro-1-isobenzofurancarboxylic acid (1) as starting products.
In all the examined cases the reaction, performed directly by heating the mixture of the reagents, leads to the formation of mixtures of 3-arylidene-phthalides (3) and 3-(arylhydroxymethyl)-phthalides (2) in variable ratios, with overall yields from 47 to 90%. 
The authors study the course of the above reported decarboxylation-condensation reaction by varying some experimental parameters, such as the type and the quantity of aldehyde, the solvent absence or presence, the reaction time and temperature.
Regarding the influence exerted by the substituents of the aldehyde (4) upon the course of the reaction the authors declare that xe2x80x9conly in the case of electrondonor groups merely the dehydration product (3) is obtained xe2x80x9c (see lines 24, 1st column, page 1519).
Besides, it seems that the reaction is advantageous only if it is performed without a solvent while it results clearly disadvantageous if it is performed in its presence. In particular in apolar solvents a 140xc2x0 C. it doesn""t occur, while in the case of polar solvents, such as e.g. dimethylsulfoxide, it exclusively leads to obtain the alcohol (2) with poor fields and only with relevant excesses (2-6 equivalents) of aldehyde (see from line 19 forward, 1st column, pag. 1519). Moreover the dehydation of (2) to (3) doesn""t occur appreciably in this solvent. Therefore from the work presented by Rolf H. Prager et al. it may be concluded that in order to obtain directly the compounds of formula (3) with significant yields the above mentioned reaction should be performed starting from electron-rich aldehydes (4) by heating in the absence of a solvent.
On the contrary we have surprisingly found that also using electron-poor aldehydes such as the pyridinecarbaldehydes, even in almost stechiometric ratio it is possible to obtain directly the corresponding arylidenephthalides with high yields if the reaction is performed in the presence of anhydrides.
With reference to this it has been hypothesized that the anhydride, besides probably acting as a dehydrator, is directly involved in the initial activation of the carboxylic function of the 3-oxo-1,3-dihydro-isobenzofuran-1-carboxylic acids.
Therefore object of the present invention is a process for preparing pyridinylidene-phthalides of formula 
wherein
Py represents a 2, 3 or 4-pyridinyl group optionally substituted by one or more substituents selected from halogen, nitro, cyano, oxo and carboxy groups;
R and R1, which may be the same or different, represent hydrogen, C1-C6 alkyl or a group OR2 wherein R2 represents a linear or branched C1-C6 alkyl, a C4-C7 cycloalkyl or a C1-C6 polyfluoroalkyl;
The bond  indicates both the isomers E and Z;
by reaction of a compound of formula 
wherein R and R1 have the above reported meanings;
with an aldehyde of formula
Py-CHO xe2x80x83xe2x80x83(III) 
wherein Py has the above reported meaning;
by heating the mixture of the compounds having formula II and III in the presence of an anhydride and optionally in admixture with a suitable solvent.
The process object of the present invention can be easily performed and it allows to obtain pyridinylidene-phthalides of formula I with good yields without using the aforesaid phosphonium salt XI.
The process object of the present invention provides for the reaction between a compound of formula II and a compound of formula III.
The compounds of formula II are known and easily obtainable for instance according to the synthetic route described in J. Chem. Soc. (1929), 200.
In the compounds of formula II the groups R and R1 have the above reported meanings.
Particularly preferred compounds of formula II are those wherein at least one between R and R1 represents OR2, even more preferred those wherein one or both between R and R1 are OCH3.
Also the starting compounds of formula III are generally known, commercially available or obtainable according to processes reported in the literature.
Particularly preferred compounds of formula III are those wherein Py represents a 4-pyridinyl group, even more preferred if Py represents a dihalosubstituted 4-pyridinyl residue. In the process object of the present invention the compounds of formula III are generally used with respect to the compounds of formula II in a molar ratio from 0.5 to 4. Preferably they are used in a ratio from 0.8 to 1.5, even more preferably from 0.9 to 1.1.
The present process is performed in the presence of an anhydride.
The term xe2x80x9canhydridexe2x80x9d means a reagent selected in the group of the organic or inorganic anhydrides, respectively derived from organic or inorganic acids, or mixed, including in this class also the acyl, alkyl and arylsulfonyl halides.
Examples of anhydrides utilizable in the present process are, in the case of the organic anhydrides, acetic, trifluoroacetic, or trifluoromethansulfonic anhydride, in the case of inorganic anhydrides, phosphoric or sulphuric anhydride or thionylchloride, while among the mixed anhydrides, acetyl, tosyl or mesyl chloride, these acyl chlorides being consider herewith as anhydrides of an organic acid and hydrogen chloride.
This, for example, acetyl chloride is the mixed anhydride of acetic acid and hydrogen chloride.
The organic anhydrides are particularly preferred.
For practical reasons acetic anhydride is preferably used.
In the process object of the present invention the above cited anhydride can be employed in a large excess as regards the starting compound of formula n acting also as solvent, for example in a molar ratio of 10:1 as regards the compound of formula II.
Alternatively the anhydride can be used as regards the compound III in a narrower molar ratio, for example from 1 to 3. In that case the reaction may request the presence of an appropriate co-solvent.
In this connection examples of usable solvents are high boiling apolar solvents such as for example the aromatic hydrocarbons, optionally chlorosubstituted.
Preferred aromatic solvents are toluene, xylene and chlorobenzene, particularly preferred is toluene.
For practical reasons the process object of the present invention is preferably performed in an excess of acetic anhydride.
Also the usage of other activating systems, such as for example the Lewis acids, or dehydrators, such as the distillation of appropriate azeotropic mixtures, falls, moreover, within the scope of the present invention as an alternative to the anhydride.
The present process is performed by heating the mixture of the compounds of formula II and III, in the presence of the anhydride and optionally of the appropriate solvent.
Preferably the reaction mixture is heated at the reflux temperature.
The process object of the present invention allows to obtain a final raw product essentially constituted by the mixture E/Z of the compounds of fomula I, usable directly without further treatment of purification.
The compounds of formula I, prepared according to the process object of the present invention, can for example be directly used in the synthesis of PDE4 inhibitors having a phthalazinic structure, as described in the already cited International application WO 00/05218.
Said compounds have the formula 
wherein
R, R1 and Py have the above reported meanings;
 is a single or double bond;
Y represents two hydrogen atoms or a group xe2x95x90O when  is a single bond, or when  is a double bond Y is hydrogen cyano, (C1-C4)-alkoxycarbonyl, amido, optionally sustituted aryl or heterocyclyl, (C1-C8)-alkyl, (C1-C8)-cyclylamino;
W is absent when  is a double bond or, when  is a single bond, it represents
a) hydrogen;
b) (C1-C6)-alkyl optionally substituted by aryl, heterocyclyl or by a group COR5 wherein R5 is hydroxy, (C1-C4)-alkoxy or hydroxyamino:
c) xe2x80x94COR6 wherein R6 is hydrogen, aryl, aryl-(C1-C6)-alkyl, optionally alkylated or monohydroxylated amino, hydroxy, (C1-C4)-alkoxy, carboxy, (C1-C4)-alkoxycarbonyl, 
or (C1-C4)-alkyl optionally substituted by a heterocycle;
d) (C1-C4)-alkylsulfonyl.
The present process is preferably applied to the synthesis of 4-pyridinyl derivatives, even more preferably to the synthesis of dihalo-substituted 4-pyridinyl derivatives. The application of the present process to the synthesis of 3-[(3,5-dichloro-4-pyridinyl)methylene]-6-methoxy-1-(3H)-isobenzofuranone is particularly preferred.
In a preferred embodiment of the process object of the present invention, the mixture of the compound II, the compound III and the anhydride is refluxed until the reaction is complete. The mixture is evaporated and the residue, recovered with the appropriate solvent and rievaporated up to dryness, can be directly used in the following step.
The process object of the present invention is advantageous chiefly for the simplicity of realization and therefore it is particularly suitable for the industrial application.
It allows to prepare the compounds of formula I with high yields and in a short time without using the above mentioned phosphonium salt XI, avoiding therefore the relative problems, such as for example the formation of unstable bromurated intermediates through exothermic reactions, the considerable increase of molecular weight and the formation of phosphineoxides.
A further reason of interest is the obtainment of a raw product usable directly in the subsequent reaction without requesting further purifications.
Besides, as regards the already cited synthetic process reported in the International application WO 00/05218, the present process allows to reduce the total number of steps starting from the same benzoic acid derivative precursor.